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Abnormal activity of a subset of transcriptional factors is a nearly universal property of tumor cells. Consistently, genetic modulation of some of these transcriptional factors (Myc, p53, HSF1, etc) has a pronounced anti-cancer effect in mice with no or minor side effects (1)-(2). However, the development of small molecules targeting transcriptional factors remains an unresolved task due to the complex interface of protein/DNA interactions. Furthermore, many transcriptional factors are functionally redundant and inhibition of one may lead to compensatory activation of another. Thus, simultaneous modulation of several tumor-related transcriptional factors is a highly desirable treatment strategy with no obvious rational solution. 

 

Presuming the existence of unknown drug-targetable mechanisms enabling the modulation of several cancer-related transcriptional factors, we used a cell-based screening approach to identify small molecules that could simultaneously activate tumor suppressor transcriptional factor, p53 and suppress pro-survival transcriptional factor, NF-kB,  thus modulating in desirable directions two major cancer treatment targets (3,4). Identified molecules, denoted curaxins (CX), demonstrated remarkable anti-cancer activity in a broad set of preclinical models.(5) 

 

A study of the mechanism of action of CXs revealed that they bind DNA without causing DNA damage, but alter the topology of the DNA double helix(5). The resulting alterations in chromatin structure lead to trapping and functional inactivation of the chromatin remodeling complex FACT (Facilitates Chromatin Transcription)(5), a histone chaperone which controls the assembly and stability of nucleosomes in embryonic stem cells and tumor cells(6,7). FACT cooperates with several transcriptional factors, involved in embryonic development, stress response, and that are commonly deregulated in cancer(7). Trapping of FACT in CX-modified chromatin blocks the activity of FACT-dependent transcriptional factors. Besides, trapping of FACT leads to p53 activation through casein kinase 2 (CK2) mediated phosphorylation of Ser392 of p53(5). Accordingly, targeting of FACT results in the simultaneous inhibition of several pro-cancerous transcriptional factors (NF-kB, Myc, HSF1, HIF1) and the activation of the anti-cancer transcriptional factor, p53 (5,8).  In line with this, we found that FACT is essential for the survival of cancer cells, including cancer and leukemia stem cells (CSC and LSC), but not for normal cells, including normal hematopoietic stem cells (HSC) (7,9). Collectively, these findings identify CXs as novel family anti-cancer small molecules. Furthermore, their mechanism of action pinpoints FACT as a novel molecular target for cancer therapeutics (7).

 

Two CX molecules currently undergoing clinical development are CBL0102 and CBL0137. CBL0102 is structurally identical to old antimalarial drug, quinacrine, widely used for the treatment and prophylaxis of malaria before WWII (10). Finding, that quinacrine or CBL0102 is potent inducer of p53 and inhibitor of NF-kB via FACT-suppressing activity, forced us to test its anti-cancer properties. We found that CBL0102 is toxic to multiple types of cancer cells in vitro and in some mouse models of cancer  (11), (12). However peculiar bio-distribution of CBL0102 in vivo with maximal accumulation in liver and skin suggested its clinical use against cancers located in liver and skin (primary and metastatic).

 

CBL0137 is proprietary structurally novel and pharmacologically optimized molecule. It is more evenly distributed between all organs in vivo, penetrates blood-brain barrier and showed strong anti-tumor activity against multiple preclinical models of cancer as monotherapy and in combinations with standard of care chemotherapy and novel targeted agents (5,9,13). 

 

 

1.Soucek, L., Whitfield, J., Martins, C. P., Finch, A. J., Murphy, D. J., Sodir, N. M., Karnezis, A. N., Swigart, L. B., Nasi, S., and Evan, G. I. (2008) Modelling Myc inhibition as a cancer therapy. Nature 455, 679-683

 

2.Dai, C., Whitesell, L., Rogers, A. B., and Lindquist, S. (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130, 1005-1018

 

3.Ben-Neriah, Y., and Karin, M. (2011) Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 12, 715-723

 

4.Gudkov, A. V., Gurova, K. V., and Komarova, E. A. (2011) Inflammation and p53: A Tale of Two Stresses. Genes Cancer 2, 503-516

 

5.Gasparian, A. V., Burkhart, C. A., Purmal, A. A., Brodsky, L., Pal, M., Saranadasa, M., Bosykh, D. A., Commane, M., Guryanova, O. A., Pal, S., Safina, A., Sviridov, S., Koman, I. E., Veith, J., Komar, A. A., Gudkov, A. V., and Gurova, K. V. (2011) Curaxins: Anticancer Compounds That Simultaneously Suppress NF-{kappa}B and Activate p53 by Targeting FACT. Sci Transl Med 3, 95ra74

 

6.Garcia, H., Fleyshman, D., Kolesnikova, K., Safina, A., Commane, M., Paszkiewicz, G., Omelian, A., Morrison, C., and Gurova, K. V. (2011) Expression of Facilitates Chromatin Transcription complex in mammalian tissues suggests FACT role in maintaining of undifferentiated state of cells. Oncotarget 2, 783-796

 

7.Garcia, H., Miecznikowski, J. C., Safina, A., Commane, M., Ruusulehto, A., Kilpinen, S., Leach, R. W., Attwood, K., Li, Y., Degan, S., Omilian, A. R., Guryanova, O., Papantonopoulou, O., Wang, J., Buck, M., Liu, S., Morrison, C., and Gurova, K. V. (2013) Facilitates chromatin transcription complex is an "accelerator" of tumor transformation and potential marker and target of aggressive cancers. Cell reports 4, 159-173

 

8.Neznanov, N., Gorbachev, A. V., Neznanova, L., Komarov, A. P., Gurova, K. V., Gasparian, A. V., Banerjee, A. K., Almasan, A., Fairchild, R. L., and Gudkov, A. V. (2009) Anti-malaria drug blocks proteotoxic stress response: anti-cancer implications. Cell Cycle 8, 3960-3970

 

9.Burkhart, C., Fleyshman, D., Kohrn, R., Commane, M., Garrigan, J., Kurbatov, V., Toshkov, I., Ramachandran, R., Martello, L., and Gurova, K. V. (2014) Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer. Oncotarget 5, 11038-11053

 

10.Gurova, K. (2009) New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents. Future Oncol 5, 1685-1704

 

11.Gurova, K. V., Hill, J. E., Guo, C., Prokvolit, A., Burdelya, L. G., Samoylova, E., Khodyakova, A. V., Ganapathi, R., Ganapathi, M., Tararova, N. D., Bosykh, D., Lvovskiy, D., Webb, T. R., Stark, G. R., and Gudkov, A. V. (2005) Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in tumors. Proc Natl Acad Sci U S A 102, 17448-17453

 

12.Dermawan, J. K., Gurova, K., Pink, J., Dowlati, A., De, S., Narla, G., Sharma, N., and Stark, G. R. (2014) Quinacrine overcomes resistance to erlotinib by inhibiting FACT, NF-kappaB, and cell-cycle progression in non-small cell lung cancer. Mol Cancer Ther 13, 2203-2214

 

13.Koman, I. E., Commane, M., Paszkiewicz, G., Hoonjan, B., Pal, S., Safina, A., Toshkov, I., Purmal, A. A., Wang, D., Liu, S., Morrison, C., Gudkov, A. V., and Gurova, K. V. (2012) Targeting FACT Complex Suppresses Mammary Tumorigenesis in Her2/neu Transgenic Mice. Cancer Prev Res (Phila) 5, 1025-1035

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